Project Summary Hypoparathyroidism is a rare disease that results from a deficiency or inability to make sufficient amounts of parathyroid hormone (PTH). Untreated or inadequately treated hypoparathyroidism leads to clinically significant mineral-related metabolic issues including hypocalcemia, which leads to heart arrhythmias, spasms of the vocal cords, and seizures. Current management of the disease for the majority of patients consists of supplemental doses of calcium and active vitamin D to manage the hypocalcemia. While this approach is intended to maintain serum calcium, it does not correct the underlying PTH deficiency and the physiological aspects of hypoparathyroidism can still occur. Moreover, supplementation is associated with long-term complications from the use of supraphysiological doses of calcium in the absence of endogenous PTH hormone, which contribute to renal function deterioration, kidney stones, soft tissue calcifications and abnormalities in bone remodeling. Natpara (PTH 1-84), recently approved by the FDA for a subset of hypoparathyroidism patients, only partially alleviates the need for vitamin supplementation due to its short half- life, and some patients still must take >10 pills/day. Clinical trials have demonstrated that if PTH(1-34) is dosed continuously via a pump in humans, it can mimic physiological levels of PTH to restore normal levels of calcium, phosphorus and markers of bone turnover. However, a pump-mediated, continuous infusion of PTH would be costly and inconvenient for patients. Extend Biosciences has developed a long-acting version of PTH(1-34) (EXT601) that could be dosed once a day and achieve a prolonged pharmacokinetic profile that approximates endogenous PTH levels. Our proprietary carrier molecule lengthens circulating half-life and improves subcutaneous bioavailability, but is small enough so as not to interfere with the activity of a peptide to which it is conjugated. SBIR Phase I results show that EXT601 has the same EC50 for receptor activation as unconjugated PTH, and a mean retention time of 10 hrs. In healthy rats, a single dose of EXT601 increases and maintains calcium levels at physiological levels for more than 24 hrs. In a rat model of hypoparathyroidism, EXT601 dosed once daily was able to maintain calcium levels, reduce phosphate levels and return markers of bone turnover to wild-type levels over the seven day study. Thus, we have identified a true PTH replacement therapy and potential breakthrough drug to treat hypoparathyroidism. The studies proposed in this Phase II application will focus on a longer term animal model and dose range finding study, as well as IND-enabling studies including toxicology/immunogenicity studies. This long-acting PTH(1-34) derivative will provide a true replacement therapy to treat hypoparathyroidism that returns calcium and phosphate to physiological levels and maintains it over the course of a day and night, thereby significantly improving quality of life for patients.